The total synthesis of phorbol represents a formidable challenge in organic chemistry. Isolated from the Euphorbiaceae plant family, phorbol is a tetracyclic tigliane diterpene that possesses a fused 5-7-6-3 ring system adorned with an array of stereogenic centers. Phorbol and derivatives containing lipophilic ester side chains are known to be potent tumor promoting agents and have also been found to induce other biological responses including HIV expression. The most notable physiological property of phorbol is its ability to bind the regulatory domain of protein kinase C (PKC) which plays a central role in cellular signal transduction. As a consequence of its structural complexity however, only two total syntheses have been reported. A practical and efficient route would be highly desirable to access both natural and unnatural phorbol derivatives. Moreover, despite the similarity of phorbol to other macrocyclic diterpenes (e.g., the daphnanes and ingenanes), a unifying synthetic strategy has not been forthcoming. Based on inspiration from Nature, a convergent total synthesis of phorbol is proposed. It has been known since 1977 that Nature constructs phorbol from a macrocyclic precursor using two transannular carbon-carbon bond forming reactions. Similarly herein, a functionalized macrocycle will provide the template for a chelation-controlled transannular allylation reaction and a conformation-controlled transannular aldol reaction. This strategy will not only serve as a viable means to access phorbol, but will shed light on the biosynthesis of these complex targets. The long-term objective of this research proposal is the efficient preparation and utilization of biologically active phorbol derivatives and other macrocyclic diterpenes for the improvement of public health. ** The development of strategies and techniques for the creation of complex molecules found in Nature is fundamentally important. Phorbol and related compounds have been shown to exhibit a range of biological responses toward the treatment of disease. This research provides an efficient and practical route to these compounds. ** [unreadable] [unreadable] [unreadable]